Pre-eclampsia or toxemia during pregnancy is one of the leading causes of maternal and infant mortality. The symptoms of pre-eclampsia typically appear after the 20th week of pregnancy and are characterized by high blood pressure, edema and protein in the urine. In severe cases there is a massive rise in blood pressure that can result in severe complications, premature delivery of the baby and death of the mother or baby.
Pre-eclampsia can vary in severity from mild to life threatening. The mild form of pre-eclampsia is usually treated with bed rest and frequent monitoring. For moderate to severe cases, hospitalization is recommended and the patient is treated with blood pressure medication or anticonvulsant medications to prevent seizures. If the condition becomes life threatening to the mother or the baby the pregnancy is terminated and the baby is delivered pre-term.
Recent research has shown that the proper development of the fetus and the placenta appears to be mediated by several growth factors. One of these growth factors is placental growth factor (PlGF) and the other is vascular endothelial growth factor (VEGF). Placental growth factor (PlGF) is a VEGF family member that is capable of inducing proliferation, migration, and activation of endothelial cells. PlGF binds as a homodimer to the Flt-1 receptor found on trophoblast cells. VEGF is an endothelial cell-specific mitogen, an angiogenic inducer, and a mediator of vascular permeability. VEGF binds as a homodimer to the homologous tyrosine kinase receptors, the fms-like tyrosine kinase (Flt-1) receptor and the kinase domain receptor (KDR).
A soluble form of the Flt-1 receptor (sFlt-1) was recently identified in the blood of pregnant women. Women with pre-eclampsia had higher levels of sFlt-1 than women with normal pregnancy. The circulating sFlt-1 receptors are believed to compete with the membrane fixed cellular Flt-1 receptors and act as a “physiologic sink” to down-regulate VEGF signaling pathways by binding to circulating PlGF and VEGF. It was postulated that women who produced large amounts of sFlt-1 early in their pregnancy were prone to develop pre-eclampsia.
Researchers have suggested several different therapeutic approaches to treat pre-eclampsia. One approach is to increase the level of PIGF and/or VEGF by injecting these compounds into the patient, or by utilizing drugs that stimulate the increased production of PIGF and/or VEGF. Increasing the amount of PlGF and VEGF in the presence of large amounts of sFlt-1 however, is analogous to driving a car and stepping on the gas while the brakes are still on. It would be preferable to reduce the level of circulating sFlt-1 so that the natural PlGF and VEGF can perform their functions.
Various means of reducing the level of circulating sFlt-1 by administering pharmaceuticals and/or anti-sFlt-1 antibody to block the binding of sFlt-1 to PlGF and/or VEGF have been proposed. However, a major difficulty with using any form of drugs is that any pharmaceutical that can target sFlt-1 will also target cellular Flt-1 and cause harm to mother and baby.
It would be preferable to develop a more safe and effective process of reducing the level of circulating sFlt-1 receptors in order to allow the natural PlGF and VEGF to perform their functions.
This invention teaches a novel method of treating pre-eclampsia by reducing the level of circulating sFlt-1 using “targeted apheresis.” The targeted apheresis process teaches a means of removing sFlt-1 using anti-sFlt-1 aptamers contained within an affinity device. It's important to note that the immobilized anti-sFlt-1 aptamers described herein are capable of binding to epitopes present on both sFlt-1 and cellular Flt-1. However, by using targeted apheresis only the circulating sFlt-1 receptors are selectively removed from the blood. The cellular Flt-1 receptors present on trophoblast cells cannot come into contact with the immobilized aptamers within the apheresis cartridge and therefore are unaffected by the apheresis process.